This project seeks evidence linking herpesvirus infections, particularly herpes simplex virus type 2 (HSV-2) to the human demyelinating disease, multiple sclerosis (MS). To be plausible, any etiologicl hypothesis must explain the clinical course, pathology, epidemiollogy and immunology of MS. A. Previous work on this project has demonstrated that: 1) HSV-2 strains, including one isolated from the brain of an MS patient, can produce optic nerve, brain and spinal cord demyelination in mice, with many points of pathological similarity to MS. 2) All of the major features of MS epidemiology may be explained by the hypothesis that MS is caused by HSV-2 in a small proportion of people infected with this agent who lack antecedent protective HSV-1 immunity. B. During FY 1983, studies published or in press establish: 1) Demyelination in experimental HSV-2 infection is part of a spectrum of disease which is consistent with current knowledge of this human agent. 2) HSV-2 persists in neurons and reactivates: may explain MS course. 3) CNS architecture and HSV-2 mechanisms may combine to produce distinctive pathological features similar to those seen in MS. C. Using virological, immunological, and morphological methods, future studies will use mouse models to aid in understanding the pathogenesis of HSV-2 infection and relation to CNS demyelination, and to devise direct tests of the proposed relation of HSV-2 infection to MS by determining: 1) Whether and under what conditions HSV-2 invades the CNS following genital infection, and if demyelinative palthology follows infection by this route. 2) Patterns of immunity to HSV-2 in mice, and effects of patterns on the outcome of CNS disease. 3) Search for direct evidence of HSV-2 antigen in human CNS tissues in MS.